Preclinical studies of many biological response modifying agents have indicated that higher drug doses do not necessarily correlate with greater degrees of either immune modulation or antitumor effects. The curve relating tumor responses to BRM dose is bell shaped such that optimal modulation occurs at doses usually well below the maximally tolerated dose. In this study we attempted to determine the optimal biologic response modifying dose of gamma interferon in patients with malignant melanoma with minimal tumor burden. This group of patients was chosen for this study so as to minimize the effects of cancer on the immune parameters we wished to monitor for this study. Immunological parameters followed in this study included natural killer cell activity, hydrogen peroxide production by monocytes, and changes in the expression of Fc receptors and HLA-DR on peripheral blood monocytes. Following intramuscular administration of gamma interferon, changes in all of these parameters were seen at doses above 0.01 mg/m2 and appeared to be maximized at the 0.1 mg/m2 dose. At a dose near the maximally tolerated dose, 0.25 mg/m2, although hydrogen peroxide production was enhanced, it declined significantly during the last week of interferon administration. We conclude that in humans, as in animals, there is an optimal biologic response modifying dose of recombinant interferon gamma below the MTD. The antitumor activity of this optimal biologic response modifying dose should be evaluated in this patient population.